Process for the preparation of gabapentin form-II

ABSTRACT

The present invention relates to a new industrial feasible process for the preparation of Gabapentin Form-II via a novel intermediate Gabapentin hemisulphate hemihydrate with out forming Gabapentin Form-III by neutralizing the Gabapentin hemisulphate hemihydrate solution with a base at higher temperatures followed by cooling to yield Gabapentin Form II with sulphate ions less than 100 ppm with respect to Gabapentin.

The present invention relates to a new industrial feasible process forthe preparation of Gabapentin Form-II via a novel intermediateGabapentin hemisulphate hemihydrate.

Gabapentin (i.e. 1-aminomethyl-1-cyclohexaneacetic acid) of the formulais the active

ingredient used for the treatment of various cerebral diseases likeepilepsy, hypokinesia including fainting and other brain trauma and ingeneral, it is deemed to produce an improvement in the cerebralfunctions.

Gabapentin and several processes for its preparation as theHydrochloride salt, sodium salts are disclosed in U.S. Pat. Nos.4,024,175 and 4,087,544.

All processes described in the prior art e.g. in US Patent ApplicationNo. US 2003/0009055, U.S. Pat. No. 6,465,689, U.S. Pat. No. 5,091,567,PCT publications WO 02/44,123, WO 02/34,709, WO 00/01,660, WO 99/14,184and European patent EP 1,174,418, yields Gabapentin hydrochloride, whichis converted to the corresponding free amino acid by neutralization witha basic ion-exchanger followed by crystallization. U.S. Pat. No.4,894,476 specifically discloses a method for converting thehydrochloride salt into a crystalline monohydrate by eluting the aqueoussolution through a basic ion-exchange resin, producing a slurry from theelute, adding an alcohol to the slurry and isolating by centrifugingfollowed by drying.

Alternate methods disclosed in U.S. Pat. No. 5,132,451, U.S. Pat. No.5,095,148, U.S. Pat. No. 5,091,567 and U.S. Pat. No. 5,068,413 involvehydrogenation of the cyano intermediate to liberate the free amino acid.

PCT publication No. WO 98/28255 discloses a method for the conversion ofGabapentin hydrochloride into Gabapentin Form-II via Gabapentin Form-IIIby elaborate multistep procedure of dissolution into a solvent,filtration of inorganics, distillation of solvent under vacuum in aheating bath at temperature below 35° C., then adding a second solvent,and neutralizing with a base at 25° C. to yield Form-III. Form-III isthen converted to Form-II by slurrying in methanol at 25° C. for 14 hrsor recrystallizing it from methanol.

The method of conversion of Gabapentin hydrochloride into Form-IIdisclosed in PCT Publication WO 98/28255 involves an additional step forthe conversion of form-III to required Form-II there by extra loss inthe yield. Moreover in the conversion of hydrochloride salt intoGabapentin with substantially very low content of chloride ions requiresextensive care and base was required. During the conversion ofGabapentin hydrochloride into free amino acid by the above method thelactam impurity was observed.

In view of all the problems still there is a requirement of anindustrial feasible process for preparation of Gabapentin Form-II withsubstantially lactam free and very low content of chloride ions.

The main object of the present invention is to provide a newindustrially feasible process for the preparation of Gabapentin Form-IIwithout the formation of Form-III.

Another object of the invention is to provide a process for thepreparation of Gabapentin Form-II free from chloride and lactamimpurities.

Yet another object of the invention is to prepare a novel intermediateGabapentin hemisulphate hemihydrate for its use in the preparation ofGabapentin Form-II.

Yet another object of the invention is to provide fingerprinting ofGabapentin hemisulphate hemihydrate using XRD, IR and chemical analysis.

Reaction of 1,1-cyclohexane diacetic acid monoamide in the presence ofalkali hypo halite followed by acidification with sulphuric acid inpresence of an organic solvent to extract the liberated sulphate saltinto that solvent. An ante solvent is added to crystallize theGabapentin sulphate salt. The separated salt is then, suspending inorganic solvent and neutralizing with a base at a specified temperaturerange, cooled to ambient temperature, followed by separation ofGabapentin Form-II, which is further purified by slurrying in ethanol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the X-ray diffraction pattern of the Gabapentin hemisulphatehemihydrate

FIG. 2 is the FTIR spectrum of the Gabapentin hemisulphate hemihydrate

FIG. 3 is the X-ray diffraction pattern of the Gabapentin Form-II

FIG. 4 is the FTIR spectrum of the Gabapentin Form-II

FIG. 5 is the X-ray diffraction pattern of the Gabapentin Form-III

FIG. 6 is the FTIR spectrum of the Gabapentin Form-III

FIG. 7 is the FTIR spectrum of the Gabapentin hydrate TABLE 1 FTIR Peaksof Gabapentin hemisulphate hemihydrate, Form-II and Form-III S. NoHemisulphate hemihydrate Hydrate Form-II Form-III 1 1714 1664 1664 21627 1624 1615 1586 3 1581 1546 1510 4 1525 1542 1476 1460 5 1461 14201420 6 1430 1400 1402 7 1392 1337 1333 8 1315 1327 1,311 9 1282 12921300 1290 10 1200 1175 1165 1180 11 1,146 1154 1,133 1160 12 1127 9681120 1115 13 986 976 974 14 941 926 928 945 15 917 880 922 926 16 901726 890 885 17 757 648 749 760 686 709 708

XRD peaks and 2 theta values: S. No Hemisulphate hemihydrate HydrateForm-II Form-III 1 6.86 6.1 7.8 6.1 2 13.7 12.2 13.3 12.1 3 17.0 16 14.916.9 4 18.0 18.3 16.6 17.6 5 20.2 19.1 16.8 18.1 6 20.6 19.8 19.5 19.9 724.2 20.7 20.2 20.8 8 24.6 24.5 21.3 24.4 9 26.2 26.4 21.8 25.1 10 26.828.4 23 28.8 11 27.7 30.7 23.5 30.2 12 29.9 32.3 25.7 30.7 13 30.8 26.931.5 14 34.0 28 15 34.7

The essential features of the present invention consists of:

-   -   Reaction of 1,1-Cyclohexane diacetic acid mono amide with alkali        hypo halite solution, acidification with sulphuric acid in        presence of a solvent    -   Extraction of the formed sulphate salt into organic layer    -   Separation of the organic layer, drying over dehydrating agents    -   Addition of an ante solvent, cooling to precipitate the        hemisulphate hemihydrate salt and its isolation    -   Dissolution of hemisulphate hemihydrate salt in a short chain        alcohol,    -   Filtration of the solution to remove the insoluble materials    -   Neutralization of the filtrate with a base at specified        temperature range to liberate the free amino acid    -   Separation of the liberated free amino acid by cooling, leaving        the formed byproduct base-salt in the mother liquor/solvent,    -   Separation of the formed Gabapentin Form-II    -   Purification of the product by slurring in ethanol in a        specified temperature range    -   Recovery of the product followed by drying

The precipitated Gabapentin and the purified Gabapentin are identifiedby XRD and IR to be polymorphic Form-II.

The 1,1-cyclohexane diacetic acid mono amide used as starting materialis prepared as per the literature (U.S. Pat. No. 4,024,175).

For the reaction of 1,1-cyclohexane diacetic acid mono amide with alkalihypo halite, the preferred alkali hypo halite Sodium hypo chloritesolution and the reaction is carried out in the temperature range ofabout −10° C. to about 5° C., with the preferred range between about −5°C. to about 5° C. Acidification of the reaction mass to a pH of about2.0 and preferably below 2.0 in the range of about 1.0 to about 1.5 iscarried out with sulphuric acid in presence of an organic solvent in atemperature range of about 15° C. to about 25° C. The preferred solventis n-Butanol.

The reaction mass is allowed to settle and the organic layer isseparated. The aqueous layer is extracted a few times with the solvent.The combined extracts is dried over dehydrating agents selected frommaterials such as anhydrous sodium sulphate, magnesium sulphate etc.

To the dried organic layer is treated with ante solvent, cooled ifrequired to precipitate the hemisulphate hemihydrate salt. The antesolvent is selected from the hydrocarbons, aromatic hydrocarbons, alkylketones, alkyl ethers, the preferred solvent being hexane, toluene,acetone, di isopropyl ether or a their mixtures. The precipitatedhemisulphate hemihydrate salt is separated by conventional methods suchas filteration, centrifugation and dried to constant weight.

The Gabapentin hemisulphate hemihydrate salt is dissolved in short chainalcohols, preferred alcohol being Ethanol, n-Butanol at about 20° C. toabout 25° C., filtered to remove the insolubles, and then raising thetemperature of the filtrate to above 70° C. preferably from about 70° C.to about 75° C., slowly neutralized with organic base. The preferredbases are tri ethyl amine, di isopropyl ethyl amine, maintain thereaction mass for 1-2 hrs at the temperature above 60° C. in thepreferable range of about 70° C to about 75° C., cooling the massgradually to about 10° C. to 25° C., preferably to about 20° C. to about25° C., stirring for about 1 to about 2 hrs followed by the separationof the precipitated free amino, washing of the wet cake with solventsuch as ethanol and drying the product at temperature preferably between45° C. to about 50° C.

The free amino acid is further purified by suspending in ethanol,raising the temperature to about 60° C. to about 65° C., maintaining thesuspension at this temperature for about one hour followed by gradualcooling and stirring for about 1-2 hrs at temperature 20° C.-25° C. Thepurified product so formed is isolated and dried to obtain Gabapentinwith chloride ions in the pharmaceutically acceptable range of 20-100ppm and lactam impurity below 0.1%.

The invention can be further illustrated by a few non-limiting examples.

EXAMPLE-I

Stage-1: Preparation of Gabapentin Hemisulphate Hemihydrate

Sodium hypochlorite solution (6.25%, 625 g) is cooled to 10° C. andsodium hydroxide flakes (51 g) is dissolved in it by stirring for 10-15min. at 10° C.-15° C. The mass is further cooled to −5° C. In a separateflask 1,1-cyclohexane diacetic acid monoamide (100 g) is dissolved in 4NSodium hydroxide solution (150 ml) at 15° C.-20° C. The amide solutionis slowly added to sodium hypochlorite solution at temperature −5° C. to−3° C. over 3 hrs. And then maintained at about 0° C. for 2 hrs. Thetemperature is then slowly raised to 20° C.-25° C. over 3 hrs andmaintained for 4 hrs at 20° C.-25° C. Sodium metabisulphite solution (5g in 10 ml water) is then added. The reaction mass is filtered to removeany undissolved material. pH of the filtrate is adjusted to 9.0 by theaddition of 1:1 dilute sulphuric acid at temperature 20° C.-25° C.n-Butanol (200 ml) is added and the pH is further adjusted to 1.5 withsulphuric acid. The reaction mass is stirred for 10-15 min. and thenallowed to settle. The layers are separated. The aq. layer is extractedwith n-Butanol (200 ml). The combined extract is dried over anhydroussodium sulphate (15 g). Di isopropyl ether (1200 ml) is slowly added atroom temperature over 30-45 min to the dried extracted layer. Thereaction mass is stirred for 1 hr and then cooled to 5° C. and stirredfor 1 hr at about 0° C.-5° C. The product is filtered, washed with diisopropyl ether (50 ml) and dried at 45° C.-50° C. to constant weight.

The yield of dry wt of Gabapentin hemisulphate hemihydrate is 85 g(Yield: 73.8%). The XRD and IR spectra are given in table-1

Stage-2: Conversion of Gabapentin Hemisulphate Hemihydrate to GabapentinForm-II

The Gabapentin hemisulphate hemihydrate salt (100 g) prepared as abovein stage-1 is suspended in ethanol (700 ml) and stirred for 30 min. atroom temperature. The insolubles are filtered and washed with ethanol(50 ml). The filtrate is heated to 70° C.-75° C. and the pH of thefiltrate is adjusted to 7.1-7.2 by slow addition of diisopropylethylamine solution (106 g in 145 ml ethanol) at 70° C.-75° C. over 60min. The reaction mass is maintained for 2 hrs at 70° C.-75° C. and thengradually cooled to 20° C.-25° C. and maintained for about 1 hr. Thefiltered product is washed with ethanol (50 ml) and dried at 45° C.-50°C. to constant weight.

Dry wt of the Gabapentin Form-II is 50 g (Yield: 67%).

Stage-3: Purification of Gabapentin Form-II

Gabapentin Form-II (50 g) prepared as above is suspended in ethanol (300ml) and the temperature is raised to 65° C. and maintained for 30 min.between 65° C.-70° C. The mass is cooled to room temperature and stirredfor 30 min. at room temperature. The filtered product is washed withethanol (25 ml) and dried at 50° C.-55° C. to constant weight.

The dry weight of Gabapentin Form-II is 45 g (Yield: 90%)

The XRD and IR of this product matched with the standard available forthe Form-II

EXAMPLE-II

Stage-1: Preparation of Gabapentin Hemisulphate Hemihydrate

Sodium hypochlorite solution (6.25%, 625 g) is cooled to 10° C. andsodium hydroxide flakes (51 g) is dissolved in the hypochlorite solutionby stirring for 10-15 min. at 10° C.-15° C. and further cooled to −5° C.In a separate flask 1,1-cyclohexane diacetic acid monoamide (100 g) isdissolved in 4N Sodium hydroxide solution (150 ml) at 15° C.-20° C. Theamide solution is slowly added to sodium hypochlorite solution attemperature −5° C. to −3° C. over 3hrs. The reaction mass is maintainedfor 2 hrs at about 0° C. and then the temperature is slowly raised to20° C.-25° C. over 3 hrs and maintained for 4 hrs at 20° C.-25° C.Sodium metabisulphite solution (5.0 g in 10 ml water) is then added. Thereaction mass filtered to remove any undissolved material. pH of thefiltrate is adjusted to 9.0 by the addition of 1:1 dil sulphuric acid attemperature 20° C.-25° C. n-Butanol (200 ml) is added and the pH isfurther adjusted to 1.5 with sulphuric acid. The mass is stirred for10-15 min., allowed to settle and the layers are separated. The aq.layer is extracted with n-Butanol (200 ml). The combined extracts aredried over anhydrous sodium sulphate (15 g). Acetone (1800 ml) is slowlyadded to the dried extracted layer at room temperature over 30-45 min.The system is then maintained for about 1 hr under stirring, cooled to5° C. and stirred further for 1 hr at 0° C.-5° C. The filtered productis washed with acetone (50 ml) and dried at 45° C.-50° C. to constantsweight. The dry wt of the Gabapentin hemisulphate hemihydrate is 82 g(Yield: 71.4%),

Which was converted to Gabapentin Form-II by following the similarprocedure as mentioned in Example-I, Stage-2 and Stage-3.

The XRD and IR spectra are given in table 1

The XRD and IR of this product matched with the standard available forthe Form-II

1. A process for the preparation of Gabapentin Form-II comprising thesteps of: reacting 1,1-cyclohexane di acetic acid mono amide with analkali hypo halite solution at a temperature of about −10° C. to about5° C., followed by acidification with sulphuric acid in presence of afirst organic solvent; extracting the formed sulphate salt into anorganic layer with a second organic solvent; separating the organiclayer, followed by drying the layer over dehydrating agents; adding anante solvent to precipitate the formed hemisulphate hemihydrate saltfollowed by its isolation; dissolving the hemisulphate hemihydrate saltin a short chain alcohol and separating an insolubles from the saltsolution to form a salt solution filtrate; neutralizing the filtratewith a base at temperature of about 70° C. to liberate the free aminoacid; isolating the liberated free amino acid by cooling, leaving formedbyproduct base-salt in the mother liquor/solvent; separating the formedGabapentin Form-II followed by purification by slurrying in ethanol attemperature of about 60° C.-70° C.; and recovering the final product byfiltering and drying to obtain Gabapentin Form-II having sulphate ionsless than 100 ppm with respect to Gabapentin.
 2. A process as claimed inclaim 1, wherein the first organic solvent is selected from n-Butanol,MIBIC, methyl ethyl ketone and THF.
 3. A process as claimed in claim 1,wherein the second organic solvent is selected from n-Butanol, MIBK, THFand methyl ethyl ketone.
 4. A process as claimed in claim 1, whereindrying of the organic layer is carried out over dehydrating agents.
 5. Aprocess as claimed in claim 1, wherein the ante solvent is selected fromacetone, toluene, n-hexane, and di isopropyl ether.
 6. A process asclaimed in claim 1, wherein the short chain alcohol is ethanol andn-Butanol.
 7. A process as claimed in claim 1, wherein the base isselected from di isopropyl ethylamine, and triethylamine.
 8. A processas claimed in claim 1, wherein the neutralization temperature is in therange of 65° C.-75° C.
 9. A process as claimed in claim 1, wherein thepurification of Gabapentin is done by slurrying in ethanol in thetemperature range 65° C.-70° C.
 10. Crystalline Gabapentin hemisulphatehemihydrate characterized by powder x-ray diffraction peaks at 2-theta6.8, 13.7, 17,0, 18.0, 20.2, 20.6, 24,2, 24.6, 26.2, 26.8, 27.7, 29.9,30,8, 34.0, and 34.7 degrees.
 11. Crystalline Gabapentin hemisulphatehemihydrate characterized by infra-red absorptions having peaks at 686,757, 901, 917, 986, 1127, 1142, 1200, 1282, 1315, 1430, 1462, 1525, 1580and 1714 cm⁻¹.
 12. A process for the preparation of Gabapentinhemisulphate hemihydrate comprising the steps of: reacting1,1-cyclohexane di acetic acid mono amide with an alkali hypo halitesolution at temperature of about −10° C. to about 5° C., followed byacidification with sulphuric acid in presence of a first is organicsolvent; extracting the formed sulphate salt into an organic layer witha second organic solvent; separating the organic layer, and drying itover dehydrating agents; adding an ante solvent to the organic layer toprecipitate a hemisulphate hemihydrate salt followed by its isolation;and isolating and drying Gabapentin hemisulphate hemihydrate.
 13. Aprocess as claimed in claim 12, wherein the first organic solvent isselected from n-Butane, MIBK, methyl ethyl ketone and THF.
 14. A processas claimed in claim 12, wherein the second organic solvent is selectedfrom n-Butanol, MIBK, THF and methyl ethyl ketone.
 15. A process asclaimed in claim 12, wherein the drying of the organic layer is carriedout over dehydrating agents.
 16. A process as claimed in claim 12,wherein the ante solvent is selected from acetone, toluene, n-hexane,and di isopropyl ether.
 17. A process as claimed in claim 12, whereinthe drying of the Gabapentin hemisulphate hemihydrate is at atemperature range of 50-60° C.
 18. (canceled)